Concentrations of endogenous digitalis-like factors (EDLF) that inhibit Na pump activity are elevated in hypertensive humans and laboratory animals, but their chemical structures, the causes of these elevations, and their role in the development of hypertension remain to be clarified. EDLF include a ouabain-like compound (OLC) that is primarily of adrenal origin, and a more recently discovered bufodienolide (i.e. a marinobufagenin-like compound or MBG), so-called since it was first isolated in toad venom. Studies in our laboratory have shown that MBG is a more rapidly acting and more potent constrictor of rat aorta than OLC, that plasma concentrations of MBG are stimulated during (a) expansion on plasma volume of dogs, (b) conditioned respiratory suppression that increases pCO2 in micropigs, and (c) intervals of voluntary hypoventilation by humans. During the current year, administration of adrenocorticotrophic hormone (which stimulates adrenocortical activity) for seven days was found to increase concentrations of MBG in plasma and inhibit Na pump activity in vascular smooth muscle of rats. This study showed that changes in Na,K-ATPase activity in vascular smooth muscle cannot necessarily be inferred from changes in erythrocyte Na,K-ATPase activity. In addition, MBG administration was found to have a greater inhibitory effect on alpha-1 isoforms of Na,K-ATPase, which predominate in vascular smooth muscle, than administration of ouabain, while ouabain had a greater inhibitory effect on alpha-3 isoforms of Na,K-ATPase, which predominate in neural tissues The ability of cells to increase genetic expression of Na,K-ATPase to compensate for inhibitory effects of sodium pump inhibitors remains to be clarified, as do the effects on vascular tone and blood pressure of sustained elevations in MBG.